THE CHANGING FACE OF VIRAL INFECTIONS AND THEIR MANAGEMENT

1. THE CHANGING FACE OF VIRAL INFECTIONS AND THEIR MANAGEMENT

Viral infections have often been considered as either minor illnesses not requiring intervention, or serious conditions for which there is no effective treatment. This perspective is changing, with the importance of seemingly

Antibiotic Policies: Theory and Practice. Edited by Gould and van der Meer Kluwer Academic / Plenum Publishers, New York, 2005

332 Sheila M. L. Waugh and William F. Carman innocuous viruses increasingly recognised. For example, rhinoviruses, a cause

of the common cold, are now known to be associated with severe lower respi- ratory disease in the immunocompromised and exacerbations of asthma (Gern and Busse, 1999; Greenberg, 2003). Similarly, though it is true that many viral infections remain untreatable, effective treatment is now available for several serious conditions, such as aciclovir in herpes simplex virus (HSV) encephali- tis, ribavirin for Lassa fever, and combination antiretroviral therapy for human immunodeficiency virus (HIV).

The increase in interest in the treatment of viral disease has been perpetu- ated both by the emergence of new viral pathogens and by the increasing prevalence of impaired immunity, either as a result of immunosuppressive treatment regimes or AIDS. Changing behaviour patterns have also led to the opportunity for increased spread of pathogens, such as hepatitis C virus (HCV) in intravenous drug users (Mathei et al., 2002).

It is important to remember that the major drive against viral infection remains defensive, based on the use of sound infection control principles and vaccination. Rigorous infection control policies have had significant impact in many situations, such as the transmission of hepatitis B virus (HBV) in renal dialysis units (UK Department of Health, 2002) and the spread of norovirus, the cause of winter vomiting disease, during outbreaks on hospital wards (Chadwick et al., 2000; McCall and Smithson, 2002). The eradication of smallpox and the elimination of poliovirus from large parts of the globe are two of the most striking examples of vaccine preventable disease, but there are many more, including the prevention of influenza virus infection (Nichol, 2003) and vaccination against HBV (Bonanni and Bonaccorsi, 2001).

There remain a limited number of antivirals, though in recent years there has been an explosive increase in licensed drugs. Nowhere is this more obvi- ous than in the development of antiretroviral therapies for the treatment of HIV, with new drugs being licensed every year and many more entering clini- cal trials (Gulick, 2003). Not only are more antiviral compounds being devel- oped and licensed, but there are also an ever-increasing number of situations where their use is being considered.

Antivirals are generally targeted at a single virus or closely related viruses, rather than a large group of viruses. Amantadine acts well against influenza A virus but has no activity against influenza B virus, and aciclovir is useful against HSV and varicella zoster virus (VZV), but is not effective as treatment for cytomegalovirus (CMV) or Epstein–Barr virus infections, despite these being members of the herpes virus family. There are two available antivirals that could reasonably be described as broad-spectrum: ribavirin (Snell, 2001) and cidofovir (Safrin et al., 1997). However, as their use is limited in many sit- uations by uncertain in vivo efficacy and, for the latter especially, a poor safety profile, it is not possible to treat a presumed viral infection empirically.

Strategies for the Rational Use of Antivirals 333

A specific virus must either be suspected clinically or found to be present on diagnostic testing before antiviral treatment can be considered. Examples of the currently available antivirals are detailed in Table 1. The majority of antiviral compounds in common current use are against viruses of

Table 1. Examples of currently available antivirals (British National Formulary, 2003; USA Food and Drug Administration, 2003)

Virus Available antivirals Main target Resistance (Molecular)

documented HSV

Aciclovir, penciclovir, valaciclovir a , Viral polymerase Yes b famciclovir a , foscarnet, cidofovir

VZV

Viral polymerase Yes c famciclovir a , foscarnet

Aciclovir, valaciclovir a ,

CMV

Viral polymerase Yes d foscarnet

Ganciclovir, valganciclovir a ,

Influenza A Amantadine Viral fusion protein Yes e Zanamivir, oseltamivir

Viral neuraminidase Yes f Influenza B Zanamivir, oseltamivir

Viral neuraminidase Yes f RSV

Ribavirin Various modes of Not yet g

action

HBV Lamivudine Viral polymerase Yes h Adefovir

Viral polymerase Not yet i Interferon

Immune system and direct antiviral effects

HCV Ribavirin and interferon/pegylated Immune system and Yes j interferon

direct antiviral effects HIV 1

Abacavir, didanosine, lamivudine, Viral reverse Yes k stavudine, tenofovir disoproxil

transcriptase zalcitabine, zidovudine Efavirenz, nevirapine

Viral reverse Yes k transcriptase Amprenivir, indinavir, lopinavir,

Viral protease Yes k nelfinavir, ritonavir, saquinavir

a Famciclovir, valaciclovir, and valganciclovir are prodrugs of penciclovir, aciclovir, and ganciclovir, respectively, with higher oral bioavailability.

b Morfin and Thouvenot (2003). c Boivin et al. (1994). d Limaye et al. (2000). e Hayden and Hay (1992).

f Gubareva et al. (1998, 2001). g Snell (2001). h Dienstag et al. (1999).

i Marcellin et al. (2003). j Pawlotsky (2000). k Pillay et al. (2000).

334 Sheila M. L. Waugh and William F. Carman the herpes family (HSV, VZV, CMV), influenza, and HIV 1. The majority are

nucleoside analogues which inhibit viral polymerases including reverse tran- scriptase. Other targets include the influenza neuraminidase and HIV protease. There is currently a great deal of interest in the development of drugs with novel targets, such as the cellular virus receptor; such an approach may help to overcome the problem of cross-resistance between drugs with a similar mode of action.

As the number of antiviral drugs grows, and in particular their increased long-term use in chronic infections such as HBV and HIV, so the problems of resistance and toxicity become more marked and more challenging.